Mucus Dehydration and Evolution of CF Lung Disease

囊性纤维化（CF）是高加索人群中最常见的致死性遗传疾病。绝 这些患者中的大多数死于肺部疾病，其特征在于气道分泌物粘稠，进行性 呼吸道阻塞和特征性细菌病原体的慢性感染。CF的自然史 包括逐渐下降和急性发作性恶化（称为恶化）。异常 已经显示盐和水穿过气道上皮的运输导致衬里的脱水 覆盖体外气道表面的液体，据推测，这种缺陷导致粘液减少 CF肺中的清除率。我们的长期目标是确定呼吸道分泌物脱水的程度 有助于CF肺病的演变，并制定维持粘液水合作用的策略， 在生命早期就开始清除。我们将通过以下具体目标来实现这一目标：（1）测试 CF肺病进展与粘液水合作用的变化相关的假设;（2）检验 假设急性加重由引发区域性疾病的触发事件（即病毒）引起 粘液清除的崩溃;和（3）测试高渗盐水安全有效地导致 持续增加粘膜纤毛清除率，减少CF患儿的气道阻塞。在 第一个目标，我们将直接测量气道分泌物的水合作用，粘液水合作用的调节剂（例如， 核苷酸、细胞因子）和粘液脱水的后果（例如粘液流变学; 细菌群落）在广泛的肺部疾病严重程度中的作用。第二个目标，我们将 前瞻性研究急性加重对体内粘膜纤毛清除率的影响， 粘液造影;我们将直接测量可能改变粘液清除（即水合作用）的粘液特性 我们将确定呼吸道病毒在触发急性呼吸道疾病中的作用， 在第三个目标中，我们将确定是否使用高渗盐水， 通过解决这种水化缺陷，可以导致粘膜纤毛清除和肺功能的持续改善， CF儿童（5-12岁）的功能，以及这种干预是否安全且耐受良好， 婴儿（年龄<3岁）CF。这些研究将直接影响我们对粘液清除的理解， CF的进展和治疗，以及更普遍地其在健康和其他气道疾病中的作用。

Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population. The vast majority of these patients die from lung disease that is characterized by thick airway secretions, progressive airways obstruction, and chronic infection with characteristic bacterial pathogens. The natural history of CF includes both a gradual decline and acute episodic deteriorations (termed exacerbations). Abnormalities in salt and water transport across the airway epithelium have been shown to cause dehydration of the lining fluid that covers airway surfaces in vitro, and it is postulated that this defect leads to reduced mucus clearance in the CF lung. Our long-term goal is to determine the extent that airway secretion dehydration contributes to the evolution of CF lung disease, and to develop strategies that maintain mucus hydration and clearance beginning early in life. We will pursue this goal through the following specific aims: (1) Test the hypothesis that CF lung disease progression is associated with changes in mucus hydration; (2) Test the hypothesis that acute exacerbations result from triggering events (i.e. viruses) that provoke a regional collapse of mucus clearance; and (3) Test the hypothesis that hypertonic saline safely and effectively leads to a sustained increase in mucociliary clearance and reduces airway obstruction in children with CF. In the first aim, we will directly measure the hydration of airway secretions, regulators of mucus hydration (e.g. nucleotides, cytokines), and the consequences of mucus dehydration (e.g. mucus rheology; evolution of bacterial communities) across a wide spectrum of lung disease severity. In the second aim, we will prospectively study the effect that acute exacerbations have on mucociliary clearance in vivo using gamma scintigraphy; we will directly measure mucus properties that may alter mucus clearance (i.e. hydration) during an exacerbation; and we will determine the role that respiratory viruses have on triggering acute exacerbations using sensitive PCR techniques, in the third aim, we will determine whether hypertonic saline, by addressing this hydration defect, can lead to sustained improvements in mucociliary clearance and lung function in children (age 5-12 years) with CF, and whether this intervention is safe and well tolerated in infants (age <3 years) with CF. These studies will directly impact our understanding of mucus clearance in the progression and treatment of CF, and more generally its role in health and other airways diseases.